In October 2007, the USFood and Drug Administration released a draft Guidance for Industry: Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice and called for public comments (1). This article summarizes the basis for the US Pharmacopeia's (USP) request to withdraw the draft guidance, provided in a detailed response to the public docket (2).
The intent of the USP performance verification test (PVT), which is used for nonsolution orally administered drug products, is to ensure continuing equivalence between the clinical trial material on which safety and efficacy conclusions were made and the manufactured article following approval. US regulatory approaches do not require postapproval reconsideration of bioequivalence for drug products, barring postapproval change. Thus, reliance on USP becomes a key if not the sole means of ensuring consistency in a drug product's performance.USP General Chapters ‹701› Disintegration and ‹711› Dissolution, and other chapters provide general procedures with acceptance criteria that can be adapted by manufacturers to specific products (3, 4). Data arising from the adaptation undergo regulatory review and, if approved, become one of the tests in the private drug product specification.
The dissolution procedure described in ‹711› requires an assembly that allows a kinetic measure of drug release over time. Combining effects from the analyst and analytic procedure, the procedure is usually performed at batch release and also as part of stability studies. The assembly is a complicated mechanical device and includes many factors that can influence results. For this reason, USP, and until recently, FDA have emphasized the importance of a periodic PVT* together with careful mechanical calibration to ensure that the combined experimental study yields consistent results.
FDA's draft guidance argues that only mechanical calibration is needed. Based on substantial research and development efforts, USP maintains instead that both PVT and mechanical calibration are critical to ensure the integrity of the dissolution procedure and that mechanical calibration alone cannot ensure the validity of dissolution results (6–15). The dissolution test system consists of the mechanical apparatus (itself composed of several components), the physical environment in which the apparatus exists, the analytical procedure, and the analyst. Mechanical calibration addresses and controls only some of the components of the apparatus.
Justification for a combined approach
Metrology. Fundamental metrology concerns the establishment of measurement units, the realization of measurement standards, and the transfer of traceability from these standards to users in society. Applied to manufacturing, metrology ensures the suitability of measurement instruments, their calibration, and quality control of measurements. In the legal sense of the term, metrology enables regulatory requirements for measurements and measuring instruments for the protection of health, public safety, and the environment, and supports decisions regarding protection of consumers and fair trade. A core concept in metrology is traceability, defined as "the property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons, all having stated uncertainties" (16). The level of traceability establishes the level of comparability of the measurement between results in any and all laboratories that conduct the procedure. USP's tests and procedures are developed with this objective in mind and form the basis for the legal recognition of USP's standards of strength, quality, and purity in the adulteration provisions of the Federal Food, Drug, and Cosmetic Act (17). USP thus works to ensure that manufacturers, for commercial purposes, and FDA, for regulatory purposes, have access to procedures that achieve a high degree of assurance in test results without regard to time and space.†
The overarching goal of metrological traceability is the transfer of accuracy (trueness) and precision throughout the measurement "ladder." The two fundamental transfer agents of this ladder are procedures with specified methods and reference materials. USP's monograph procedures are frequently grounded in reference materials (e.g., official USP reference standards), with the understanding that the relationship between the procedure for the measurand (the material being examined) is closely linked to the reference material reflective of that measurand. At times, USP uses informally the terms "vertical standards" for the article under test and "horizontal standards" for the monograph's procedures. A key example of horizontal documentary and reference material standards is the dissolution procedure, described in ‹711›. There is a metrologic aspect to the dissolution procedure because a concentration is determined and can be traced to the base SI units of mass (kilogram). USP, however, notes that the kinetic aspects of the dissolution procedure are not well-grounded in metrology (i.e., there is no absolute number from the kinetic study that can be traced to an SI unit). In this regard, the dissolution procedure has the kinetic character of an enzyme assay that yields results in units per mass rather than in SI units alone. This does not mean that such grounding could not be improved, nor does it mean that the procedure is without value. The complex character of an assembly in fact requires careful consideration of horizontal standards to ensure acceptable results.